milnacipran (Rx)

Brand and Other Names:Savella
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Dosing & Uses


Dosage Forms & Strengths


  • 12.5mg
  • 25mg
  • 50mg
  • 100mg


12.5 mg PO once on day 1, then 25 mg/day divided q12hr on days 2-3, then 50 mg/day divided q12hr on days 4-7, then 100 mg/day divided q12hr thereafter; not to exceed 200 mg/day

Therapy discontinuation

  • When discontinuing antidepressant therapy that have lasted for more than 3 weeks, taper dose gradually over 2-4 weeks; this will minimize withdrawal symptoms and help detect reemerging symptoms
  • If intolerable withdrawal symptoms occur, resume previously prescribed dose; may also decrease dose at more gradual rate; patients on long-term treatment (>6 weeks) may benefit from tapering over >3 months

Switching to or from MAO inhibitors

  • Allow five or more days to elapse between milnacipran discontinuation and initiation of MAO inhibitor
  • Allow 14 days to elapse between MAO inhibitor discontinuation and initiation of milnacipran
  • Severe renal impairment: may increase to 50 mg BID if tolerated

Dosing Modifications

Renal impairment

  • Mild (CrCl 50-80 mL/min): No dosage adjustment required
  • Moderate (CrCl 30-49 mL/min): Use with caution
  • Severe (CrCl 5-29 mL/min): Reduce maintenance dosage by 50% (ie, to 50 mg/day divided q12hr)
  • End-stage renal disease (ESRD): Use not recommended

Hepatic impairment

  • Mild or moderate (Child-Pugh A or B): No dosage adjustment required
  • Severe (Child-Pugh C): Caution advised

<17 years: Safety and efficacy not established



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            Adverse Effects


            Nausea (37%)

            Headache (18%)

            Constipation (16%)

            Hot flush (12%)

            Insomnia (12%)

            1-10% (selected)









            Frequency Not Defined

            Abnormal bleeding

            Depression (worsening)

            Serotonin syndrome

            Suicidal thoughts

            Withdrawal signs or symptoms

            Postmarketing Reports

            Hematologic disorders: Leukopenia, neutropenia, thrombocytopenia

            Cardiac disorders: Supraventricular tachycardia, takotsubo cardiomyopathy

            Eye disorders: Accommodation disorder

            Endocrine disorders: Hyperprolactinemia

            Gastrointestinal disorders: Acute pancreatitis

            Hepatobiliary disorders: Hepatitis

            Metabolic and nutritional disorders: Anorexia, hyponatremia

            Musculoskeletal and connective tissue disorders: Rhabdomyolysis

            Neurologic disorders: Convulsions (including grand mal), loss of consciousness, parkinsonism

            Psychiatric disorders: Aggression, anger, delirium, hallucination, homicidal ideation

            Renal and urinary disorders: Acute renal failure

            Reproductive system and breast disorders: Galactorrhea

            Skin disorders: Erythema multiforme, Stevens-Johnson syndrome

            Vascular disorders: Hypertensive crisis



            Black Box Warnings

            In short-term studies, antidepressants increased risk of suicidal thinking and behavior in children, adolescents, and young (<24 years) adults taking antidepressants for major depressive disorders and other psychiatric illnesses

            This increase was not seen in patients aged >24 years; slight decrease in suicidal thinking was seen in adults aged >65 years

            In children and young adults, risks must be weighed against benefits of taking antidepressants

            Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; this should be done during initial 1-2 months of therapy and dosage adjustments

            Patient’s family should communicate any abrupt behavioral changes to healthcare provider

            Worsening behavior and suicidal tendencies that are not part of presenting symptoms may necessitate discontinuance of therapy

            Drug is not approved for use in pediatric patients


            Concomitant use of monoamine oxidase inhibitors (MAOIs), use of MAOIs within 5 days after discontinuance of milnacipran, or initiation of milnacipran within 14 days after discontinuance of MAOIs

            Patients being treated with linezolid or intravenous methylene blue


            Milnacipran is serotonin-norepinephrine reuptake inhibitor (SNRI) similar to those used for depression and other psychiatric disorders; monitoring and close observation for clinical worsening, suicidality, and unusual changes in behavior are necessary, especially during first few months of treatment and when dosage is increased or decreased (see Black Box Warnings)

            Potentially life-threatening serotonin syndrome has been reported with both SNRIs and selective serotonin reuptake inhibitors (SSRIs) when these agents are taken alone, but especially when they are coadministered with other serotonergic agents; thus, patient medications should be thoroughly reviewed for other serotonergic drugs (eg, tryptophan supplements, tramadol, serotonin agonists [triptans], MAOIs, tricyclic antidepressants [TCAs], SSRIs, methylene blue, buspirone, amphetamines, linezolid)

            May increase blood pressure (BP) or heart rate (HR); BP should be controlled before initiation of milnacipran; BP and HR should be monitored while patient is taking drug; consider dose reduction or discontinuation of therapy in patients with sustained hypertension or tachycardia during therapy

            SSRIs and SNRIs may impair platelet aggregation and increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and GI hemorrhage to life-threatening hemorrhage; concomitant use of aspirin, NSAIDs, warfarin, other anticoagulants, or other drugs known to affect platelet function may add to this risk

            Neonates exposed to SNRIs or SSRIs late in third trimester are at risk for complications such as feeding difficulties, irritability, and respiratory problems

            Prescription should be written for smallest amount consistent with good patient care; alert family members to monitor for emergence of suicidality, including panic attacks, hostility, irritability, insomnia, anxiety, agitation, mania and hypomania

            Bone fracture reported with antidepressant treatment; consider possibility of fracture in patients that present with unexplained bone pain, swelling, or bruising

            Use caution in patients with history of seizures

            Moderate renal impairment

            Avoid use in severe hepatic impairment; discontinue therapy with signs of hepatic dysfunction or jaundice; do not reinitiate therapy unless another source or cause identified

            Avoid concomitant use in patients with substantial alcohol use or chronic liver disease

            Withdrawal symptoms reported in patients when discontinuing treatment; gradual dose reduction recommended

            Pupillary dilation that occurs following use of SNRI drugs including milnacipran may trigger angle closure attack in patients with anatomically narrow angles who do not have a patent iridectomy; for patients who have not had an iridectomy for narrow angle glaucoma risk factors, consider performing evaluation

            Patietns with history of obstructive uropathies may experience higher rates of genitourinary adverse drug reactions (ADRs)

            ESRD: Use not recommended

            Development of SIADH and hyponatremia reported with SSRIs and SNRIs, predominantly in the elderly; volume depletion and/or concurrent use of diuretics may increase risk

            May cause urinary hesitance; advise patients to report urinary symptoms or difficulties; use caution in patients with history of lower urinary tract disorders, including benign prostatic hyperplasia or prostatitis

            May worsen psychosis in patients with mood disorders; a shift to mania or hypomania reported with bipolar disorder; avoid monotherapy in patients with bipolar disorder; screen prospective patients for bipolar disorder when presenting with depressive symptoms


            Pregnancy & Lactation

            Pregnancy category: C

            Lactation: Drug is excreted in human milk; peak breast milk concentration is observed within 4 hours after maternal dose, and estimated infant exposure is 5% of maternal dose; limited data are available regarding infant exposure, but caution is advised

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.



            Mechanism of Action

            SNRI; has no affinity for other neurotransmitter receptors (including gamma-aminobutyric acid [GABA], beta-adrenergic, opiate, histaminergic, and benzodiazepine receptors) and has no MAOI activity


            Bioavailability: 85-90%

            Peak plasma time: 2-4 hr


            Protein bound: 13%

            Vd: 400 L


            Metabolized to several metabolites


            Half-life: L-isomer, 6-8 hr; D-isomer, 8-10 hr

            Excretion: Urine (55%)





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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.